Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, 34134, Republic of Korea.
Department of Dentistry, Seoul National University, Seoul, 03080, Republic of Korea.
Int J Obes (Lond). 2019 Sep;43(9):1769-1782. doi: 10.1038/s41366-019-0376-2. Epub 2019 May 13.
Neuronal growth regulator 1 (NEGR1) is a glycosylphosphatidylinositol-anchored membrane protein that mediates neural cell communication and synapse formation. Multiple genome-wide association studies have reported that variations in NEGR1 are associated with human body weight control. Recently, we found that NEGR1 is involved in intracellular cholesterol trafficking, suggesting that it performs a non-central nervous system (CNS) function associated with human obesity.
We compared peripheral tissues such as the adipose, liver, and skeletal muscle tissues of Negr1 and Negr1 (wild-type [WT]) C57BL/6 mice (n = 5-14). Intracellular lipid content was measured, and lipid accumulation was visualized by staining tissue cross-sections with lipid-specific stains. Muscle capacity of the WT and Negr1 mice was determined by performing a treadmill endurance test, and muscle fiber size was examined. Plasma glucose and insulin levels were measured, and glucose and insulin tolerance tests were performed.
The Negr1 mice showed a significant increase in fat mass (1.5-fold increase in the epididymal white adipose tissue, p = 0.000002), with abnormally enlarged adipose cells, compared with the WT mice. Primary adipocytes of the Negr1 mice contained enlarged cytosolic lipid droplets (p = 0.049). Moreover, these mice showed significant hepatic lipid accumulation (2.3-fold increase, p = 0.043). Although the Negr1 mice did not show a significant change in plasma lipoprotein level, they showed a >1.3-fold increase in a serum glucose (p = 0.0002) and insulin (p = 0.016) levels. Moreover, the Negr1 mice showed decreased muscle capacity, as indicated by a decrease in muscle mass (p = 0.000003).
These results indicate that NEGR1 deficiency induces abnormal fat deposition in various peripheral cells, especially fat and liver tissue cells, and suggest that NEGR1 is a potential molecular target for designing anti-obesity drugs to regulate body weight both centrally and peripherally.
神经元生长调节因子 1（NEGR1）是一种糖基磷脂酰肌醇锚定的膜蛋白，介导神经细胞通讯和突触形成。多项全基因组关联研究报告称，NEGR1 的变异与人体体重控制有关。最近，我们发现 NEGR1 参与细胞内胆固醇运输，表明它具有与人类肥胖相关的非中枢神经系统（CNS）功能。
我们比较了 Negr1 和 Negr1（野生型 [WT]）C57BL/6 小鼠的外周组织，如脂肪、肝脏和骨骼肌组织（n=5-14）。测量细胞内脂质含量，并通过用脂质特异性染色剂染色组织切片来可视化脂质积累。通过进行跑步机耐力测试来确定 WT 和 Negr1 小鼠的肌肉能力，并检查肌肉纤维大小。测量血浆葡萄糖和胰岛素水平，并进行葡萄糖和胰岛素耐量测试。
与 WT 小鼠相比，Negr1 小鼠的脂肪量明显增加（附睾白色脂肪组织增加约 1.5 倍，p=0.000002），脂肪细胞异常增大。Negr1 小鼠的原代脂肪细胞含有增大的胞质脂质滴（p=0.049）。此外，这些小鼠还表现出明显的肝脂质积累（增加约 2.3 倍，p=0.043）。尽管 Negr1 小鼠的血浆脂蛋白水平没有明显变化，但它们的血清葡萄糖（p=0.0002）和胰岛素（p=0.016）水平增加了 1.3 倍以上。此外，Negr1 小鼠的肌肉能力下降，表现为肌肉质量减少（p=0.000003）。
这些结果表明，NEGR1 缺乏会导致各种外周细胞（尤其是脂肪和肝脏组织细胞）异常脂肪沉积，并表明 NEGR1 是设计中枢和外周调节体重的抗肥胖药物的潜在分子靶标。
